Optical coherence tomography (OCT) is a micron scale high-resolution optical technology that can provide real-time in vivo images noninvasively. The ability to detect airway mucosal and submucosal injury rapidly will be valuable for a range of pulmonary applications including assessment of acute inhalation smoke and burn injury. OCT has the potential ability to monitor the progression of airway injury changes including edema, hyperemia, and swelling, which are critical clinical components of smoke-inhalation injury. New Zealand white male rabbits exposed to cold smoke from standardized unbleached burned cotton administered during ventilation were monitored for 6 h using a 1.8-mm diameter flexible fiberoptic longitudinal probe that was inserted through the endotracheal tube. The thickness of the epithelial, mucosal, and submucosal layers of the rabbit trachea to the tracheal cartilage was measured using a prototype superluminescent diode OCT system we constructed. OCT was able to detect significant smoke-injury-induced increases in the thickness of the tracheal walls of the rabbit beginning very shortly after smoke administration. Airway wall thickness increased to an average of 120% (+/-33%) of baseline values by 5 h following exposure. OCT is capable of providing real-time, noninvasive images of airway injury changes following smoke exposure. These studies suggest that OCT may have the ability to provide information on potential early indicators of impending smoke-inhalation-induced airway compromise.